The purpose of the program is to study immunobiology and immunopathology of type I diabetes in the BB rat and the NOD mouse. The program is based on the following general hypothesis: tissue specific autimmunity in type I diabetes stems from a defect in the development of the T cell repertoire during ontogeny in the thymus, and leads to the presence of clones of T cells in the periphery able to recognize antigen on islet beta cells. In conjunction with this developmental defect in the immune system there exists an abnormality in the target tissue resulting in sensitivity of the islet tissue to disease. Project 1: (Biology of the thymus in the BB rat). Tests the hypothesis that a T cell defect of thymic origin is involved in disease development in these animals. Project 2: (Definition of islet cell antigens) is based on the hypothesis that islet beta cells have on their surface a molecule or molecules that are recognized as antigens by T cells. This project sets out to examine the nature of beta cell surface autoantigens using monoclonal antibodies to islet cells and islet reactive T cell lines. Project 3: (Pathogenesis of the disease process) will test the hypothesis that autoimmune diabetes in the NOD mouse results from CD4 T cell dependent inflammatory tissue damage, and that the approximate cause of diabetes is free radical mediated beta cell damage. project 4: (Thymic regulation of the peripheral repertoire in the NOD mouse) will test the hypothesis that the structure of MHC class II antigen of the NOD mouse is directly responsible for the generation of a set of T cell clone(s) which are responsible for the expression of diabetes in this mouse. Project 5: (Genetic control of the disease process) is based on the hypothesis which predicts that the introduction of certain class II MHC genes will prevent the development of aberrant T cells, the recognition of which is required for the expression of the disease process. The major thrust of this project is the development of congenic lines with different elements of the NOD MHC expressed individually on the genetic background of the NOD mouse. Project 6: (Manipulation of the diabetic phenotype) tests the hypothesis that the expression of diabetes in the NOD mouse results from inadequate development of self-tolerance, and that stem cell engraftment or the elimination of T cell subsets during the developmental phase of the animal will influence the expression of diabetes in the NOD mouse.